Traumatic brain injury (TBI) is a leading cause of mortality and disability in younger adults worldwide, with an estimated US incidence of 1.5 million per year in the general population. The annual economic costs in the US were estimated at US$76.5 billion. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all TBIs, and a significant portion of mTBI patients suffer from long lasting o even permanent post-concussive syndromes. Repetitive mTBI from multiple concussions is of particular concern for individuals engaged in contact sports or in military operations. Currently no pharmacological therapy is available that augments functional recovery or prevents long-term neuropsychological symptoms associated with TBI. Transforming growth factor-? (TGF-?) is an important injury response factor in the brain and has been implicated in various neurological diseases and in TBI. Using our recently developed mouse model of repetitive mTBI, our preliminary data show that TGF-? is dysregulated after repetitive mTBI and that SRI-011381, a novel small molecule TGF-? agonist developed at Stanford University, when applied 24 h after injury, reduces cognitive deficits and neuroinflammation. Based on these findings, we propose to investigate the long-term changes and the role of TGF-? signaling in repetitive mTBI and to investigate whether activating TGF-? signaling through SRI- 011381 can reduce long-term cognitive deficits and neuropathology associated with repetitive mTBI. In addition to the wide therapeutic time window of SRI-011381, our proposal builds and expands on the results from the extensive preclinical efficacy, pharmacology and toxicology studies in which our lab has been involved. Our ultimate goal is to develop SRI-011381 for clinical testing as a therapeutic for patients with repetitive mTBI. We hope that our clinically relevant experimental design, along with the advantages of SRI-011381 will increase the likelihood of success in clinical testing.